DESCRIPTION: (Adapted from the application) Small arteries exist in a contracted state from which they can either constrict or dilate, depending on the local tissue blood flow requirements. Intravascular pressure causes many resistance arteries to develop (myogenic) tone which is further modulated by constricting and dilating substances. Coronary artery tone is regulated by both voltage-dependent Ca2+ channels (Ca2+ enters the cell upon membrane depolarization) and by K+ channels. If activated, K+ channels cause hyperpolarization and vasodilation, and if inhibited, they will cause vasoconstriction. The applicant's long term goal is to investigate the role of K+ channels in regulating coronary artery tone. The first specific aim of the proposal is to test the hypothesis that inward rectifier K+ channels (KIR channels) are important in regulating myogenic tone in coronary arteries, and that they are modulated by endogenous compounds such as adenosine. Preliminary data provided in support of this aim suggests that KIR channels are important in regulating coronary artery tone, as inhibiting them causes constriction of pressurized arteries. Also, adenosine which is released from cardiac myocytes in conditions of ischemia, dilates coronary arteries in part by opening KIR channels. These two findings form the basis of other experiments investigating how KIR channels are involved in regulating coronary artery diameter, and how adenosine activates these channels. The second aim of the proposal is to test the hypothesis that activation of KCa channels by nitric oxide (NO) and adenosine induces vasodilation in coronary arteries. Preliminary data suggests that KCa channels are modulated by many endogenous substances, and therefore are important in modulating coronary artery diameter. Experiments described in this proposal will investigate how two very important vasodilators, adenosine and NO activate these channels. K+ channels integrate with other ion channels, and the endothelium, to control arterial diameter. Whole-cell and single-channel patch clamp current measurements in isolated freshly dissociated cells from coronary arteries will be used to provide information as to how these channels are regulated, either directly, or by secondary messenger systems. Clinically, this study should significantly advance our understanding of the control of arterial tone and therefore the regulation of coronary blood flow. These K+ channels, or factors such as NO and adenosine that activate them to cause vasodilation, may be damaged in the diseased and ischemic heart. This would greatly reduce the ability of the coronary arteries to dilate, and limit blood flow to the myocardium. The proposal also has the potential to provide a new foundation for the development of therapeutic agents to treat coronary vasospasm and other coronary heart diseases associated with myocardial ischemia.